Triarylimidazoles

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof:                    
     wherein R 1 , R 2  and R 3  are various substituent groups; and 
     one of X 1  and X 2  is N or CR′, and the other is NR′ or CHR′ wherein R′ is hydrogen, OH, C 1-6 alkyl, or C 3-7 cycloalkyl; or when one of X 1  and X 2  is N or CR′ then the other may be S or O; 
     and their use as pharmaceuticals.

This application is a 371 of PCT/US00/09147 filed Apr. 6, 2000, whichclaims the benefit of priority to provisional application 60/128,687filed Apr. 9, 1999.

This invention relates to pyridyl substituted triarylimidazoles whichare inhibitors of the transforming growth factor, (“TGF”)-β signalingpathway, in particular, the phosphorylation of smad2 or smad3 by thetype I or activin-like kinase (“ALK”)-5 receptor, methods for theirpreparation and their use in medicine, specifically in the treatment andprevention of a disease state mediated by this pathway.

TGF-β1 is the prototypic member of a family of cytokines including theTGF-βs, activins, inhibins, bone morphogenetic proteins andMüllerian-inhibiting substance, that signal through a family of singletransmembrane serine/threonine kinase receptors. These receptors can bedivided in two classes, the type I or activin like kinase (ALK)receptors and type II receptors. The ALK receptors are distinguishedfrom the type II receptors in that the ALK receptors (a) lack theserine/threonine rich intracellular tail, (b) possess serine/threoninekinase domains that are very homologous between type I receptors, and(c) share a common sequence motif called the GS domain, consisting of aregion rich in glycine and serine residues. The GS domain is at theamino terminal end of the intracellular kinase domain and is criticalfor activation by the type II receptor. Several studies have shown thatTGF-β signaling requires both the ALK and type II receptors.Specifically, the type II receptor phosphorylates the GS domain of thetype I receptor for TGF-β, ALK5, in the presence of TGF-β. The ALK5, inturn, phosphorylates the cytoplasmic proteins smad2 and smad3 at twocarboxy terminal serines. Generally it is believed that in many species,the type II receptors regulate cell proliferation and the type Ireceptors regulate matrix production. Therefore, preferred compounds ofthis invention are selective in that they inhibit the type I receptorand thus matrix production, and not the type I receptor mediatedproliferation.

Activation of the TGF-β1 axis and expansion of extracellular matrix areearly and persistent contributors to the development and progression ofchronic renal disease and vascular disease. Border W. A., Noble N. A.,N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. Further, TGF-β1 playsa role in the formation of fibronectin and plasminogen activatorinhibitor-1, components of sclerotic deposits, through the action ofsmad3 phosphorylation by the TGF-β1 receptor ALK5. Zhang Y., Feng X. H.,Derynck R., Nature, Aug. 27, 1998; 394(6696):909-13; Usui T., Takase M.,Kaji Y., Suzuki K., Ishida K., Tsuru T., Miyata K., Kawabata M.,Yamashita H., Invest. Ophthalmol. Vis. Sci., October 1998; 39(11):1981-9.

Progressive fibrosis in the kidney and cardiovascular system is a majorcause of suffering and death and an important contributor to the cost ofhealth care. TGF-β1 has been implicated in many renal fibroticdisorders. Border W. A., Noble N. A., N. Engl. J. Med., Nov 10, 1994;331(19):1286-92. TGF-β1 is elevated in acute and chronicglomerulonephritis, Yoshioka K., Takemura T., Murakami K., Okada M.,Hino S., Miyamoto H., Maki S., Lab. Invest., February 1993;68(2):154-63, diabetic nephropathy, Yamamoto, T., Nakamura, T., Noble,N. A., Ruoslahti, E., Border, W. A., (1993) PNAS 90:1814-1818, allograftrejection, HIV nephropathy and angiotensin-induced nephropathy, BorderW. A., Noble N. A., N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. Inthese diseases the levels of TGF-β1 expression coincide with theproduction of extracellular matrix. Three lines of evidence suggest acausal relationship between TGF-β1 and the production of matrix. First,normal glomeruli, mesangial cells and non-renal cells can be induced toproduce extracellular-matrix protein and inhibit protease activity byexogenous TGF-β1 in vitro. Second, neutralizing anti-bodies againstTGF-β1 can prevent the accumulation of extracellular matrix in nephriticrats. Third, TGF-β1 transgenic mice or in vivo transfection of theTGF-β1 gene into normal rat kidneys resulted in the rapid development ofglomerulosclerosis. Kopp J. B., Factor V. M., Mozes M., Nagy P.,Sanderson N., Bottinger E. P., Klotman P. E., Thorgeirsson S. S., LabInvest, June 1996; 74(6):991-1003. Thus, inhibition of TGF-β1 activityis indicated as a therapeutic intervention in chronic renal disease.

TGF-β1 and its receptors are increased in injured blood vessels and areindicated in neointima formation following balloon angioplasty, SaltisJ., Agrotis A., Bobik A., Clin Exp Pharmacol Physiol, March 1996;23(3):193-200. In addition TGF-β1 is a potent stimulator of smoothmuscle cell (“SMC”) migration in vitro and migration of SMC in thearterial wall is a contributing factor in the pathogenesis ofatherosclerosis and restenosis. Moreover, in multivariate analysis ofthe endothelial cell products against total cholesterol, TGF-β receptorALK5 correlated with total cholesterol (P<0.001) Blann A. D., Wang J.M., Wilson P. B., Kumar S., Atherosclerosis, February 1996;120(1-2):221-6. Furthermore, SMC derived from human atheroscleroticlesions have an increased ALK5/TGF-β type II receptor ratio. BecauseTGF-β1 is over-expressed in fibroproliferative vascular lesions,receptor-variant cells would be allowed to grow in a slow, butuncontrolled fashion, while overproducing extracellular matrixcomponents McCaffrey T. A., Consigli S., Du B., Falcone D. J., SanbornT. A., Spokojny A. M., Bush H. L., Jr., J Clin Invest, December 1995;96(6):2667-75. TGF-β1 was immunolocalized to non-foamy macrophages inatherosclerotic lesions where active matrix synthesis occurs, suggestingthat non-foamy macrophages may participate in modulating matrix geneexpression in atherosclerotic remodeling via a TGF-β-dependentmechanism. Therefore, inhibiting the action of TGF-β1 on ALK5 is alsoindicated in atherosclerosis and restenosis.

TGF-β is also implicated in peritoneal adhesions Saed G. M., Zhang W.,Chegini N., Holmdahl L., and Diamond M P., Wound Repair Regeneration.7(6):504-510, 1999 November-December. Therefore, inhibitors of ALK5would be beneficial in preventing peritoneal and sub-dermal fibroticadhesions following surgical procedures.

Surprisingly, it has now been discovered that a class of 2-pyridylsubstituted triarylimidazoles of formula (I), function as potent andselective non-peptide inhibitors of ALK5 kinase and therefore, haveutility in the treatment and prevention of various disease statesmediated by ALK5 kinase mechanisms, such as chronic renal disease, acuterenal disease, wound healing, arthritis, osteoporosis, kidney disease,congestive heart failure, ulcers, occular disorders, corneal wounds,diabetic nephropathy, impaired neurological function, Alzheimer'sdisease, trophic conditions, atherosclerosis, peritoneal and sub-dermaladhesion, any disease wherein fibrosis is a major component, including,but not limited to lung fibrosis and liver fibrosis, and restenosis.

According to the invention there is provided a compound of formula (I)or a pharmaceutically acceptable salt thereof:

wherein R₁ is naphthyl, anthracenyl, or phenyl optionally substitutedwith one or more substituents selected from the group consisting ofhalo, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkyl, —O—(CH₂)_(n)—Ph,—S—(CH₂)_(n)—Ph, cyano, phenyl, and CO₂R, wherein R is hydrogen orC₁₋₆alkyl and n is 0, 1, 2 or 3; or R₁ is phenyl fused with an aromaticor non-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to two heteroatoms, independently selected fromN, O and S;

R₂ is H, NH(CH₂)_(n)—Ph or NH—C₁₋₆alkyl, wherein n is 0, 1, 2 or 3;

R₃ is CO₂H, CONH₂, CN, NO₂, C₁₋₆alkylthio, —SO₂—C₁₋₆alkyl, C₁₋₆alkoxy,SONH₂, CONHOH, NH₂, CHO, CH₂OH, CH₂NH₂, or CO₂R, wherein R is hydrogenor C₁₋₆alkyl; and

one of X₁ and X₂ is N or CR′, and the other is NR′ or CHR′ wherein R′ ishydrogen, OH, C₁₋₆alkyl, or C₃₋₇cycloalkyl; or when one of X₁ and X₂ isN or CR′ then the other may be S or O.

As used herein, the double bond indicated by the dotted lines of formula(I), represent the possible tautomeric ring forms of the compoundsfalling within the scope of this invention. It will be understood thatwhen one of X₁ and X₂ is carbon and the other is nitrogen, then thedouble bond could be either to the carbon or the nitrogen. When X₁ andX₂ are both carbon, then the double bond could be to either X₁ or X₂.When X₁ and X₂ are both nitrogen, then the double bond is to theunsubstituted nitrogen.

Preferably R₁ is optionally substituted naphthyl or phenyl. Morepreferably R₁ is phenyl optionally substituted with one or moresubstituents selected from the group consisting of halo, C₁₋₆alkoxy,C₁₋₆alkylthio, and phenyl; or R₁ is phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to two heteroatoms, independently selected fromN, O and S, for example R₁ represents benzo[1,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, benzoxazolyl, benzothiazolyl,benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl ordihydrobenzofuranyl.

Preferably, R₂ is positioned ortho to the nitrogen of the pyridyl ring.More preferably R₂ is hydrogen.

Preferably R₃ is CO₂H, CONH₂, CN, NO₂, SONH₂, CONHOH, NH₂, CHO, CH₂OH orCH₂NH₂.

Preferably one of X₁ and X₂ is N or CR′, and the other is NR′ or CHR′wherein R′ is hydrogen, C₁₋₆alkyl, or C₃₋₇cycloalkyl, provided that atleast one of X₁ and X₂ is N or NR′; or one of X₁ and X₂ is N and theother is O. More preferably one of X₁ and X₂ is N and the other is NR′.

Preferably each R′ is hydrogen.

Specific compounds of the invention which may be mentioned include thefollowing and pharmaceutically acceptable salts thereof:

4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1-hydroxy-1H-imidazol-2-yl]benzonitrile;

4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzonitrile;

4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoic acid;

Methyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate;

Ethyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate

4-(4-Benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;

2-[4-Benzo[1,3]dioxol-5-yl-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine;

3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine;

4-[4-(4-Fluorophenyl)-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine;

4-[4-(4-Fluorophenyl)-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenyl]methanol;

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide;

4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile;

4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

4-[4-(2,3-Dihydro-benzofuran-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

3-[4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;

4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzonitrile;

4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;

4-[4-(4-Methoxyphenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile;

4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-4-pyridin-2-yl-1H-imidazol-2-yl]benzamide;

4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzonitrile;

4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzamide; and

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-pyrrol-2-yl)benzamide.

Suitable, pharmaceutically acceptable salts of the compounds of formula(I) include, but are not limited to, salts with inorganic acids such ashydrochloride, sulfate, phosphate, diphosphate, hydrobromide, andnitrate, or salts with an organic acid such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, palmitate, salicylate, andstearate.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms. The different isomeric forms may beseparated or resolved one from the other by conventional methods, or anygiven isomer may be obtained by conventional synthetic methods or bystereospecific or asymmetric syntheses.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably at least 10% of a compound of the formula (I)or pharmaceutically acceptable derivative thereof.

The term “C₁₋₆alkyl” as used herein whether on its own or as part of alarger group e.g. C₁₋₆alkoxy, means a straight or branched chain radicalof 1 to 6 carbon atoms, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

C₁₋₆ haloalkyl groups may contain one or more halo atoms, a particularC₁₋₆ haloalkyl group that may be mentioned in CF₃.

The terms “halo” or “halogen” are used interchangeably herein to meanradicals derived from the elements chlorine, fluorine, iodine andbromine.

The term “C₃₋₇cycloalkyl” as used herein means cyclic radicals of 3 to 7carbons, including but not limited to cyclopropyl, cyclopentyl andcyclohexyl.

The term “aryl” as used herein means 5- to 14-membered substituted orunsubstituted aromatic ring(s) or ring systems which may include bi- ortri-cyclic systems, including, but not limited to phenyl and naphthyl.

The term “ALK5 inhibitor” as used herein means a compound, other thaninhibitory smads, e.g. smad6 and smad7, which selectively inhibits theALK5 receptor preferentially over p38 or type II receptors.

The term “ALK5 mediated disease state” as used herein means any diseasestate which is mediated (or modulated) by ALK5, for example a diseasewhich is modulated by the inhibition of the phosphorylation of smad 2/3in the TGF-1β signaling pathway.

The term “ulcers” as used herein includes, but is not limited to,diabetic ulcers, chronic ulcers, gastric ulcers, and duodenal ulcers.

The compounds of formula (I) can be prepared by art-recognizedprocedures from known or commercially available starting materials. Ifthe starting materials are unavailable from a commercial source, theirsynthesis is described herein, or they can be prepared by proceduresknown in the art.

Specifically, compounds of formula (I) wherein one of X₁ and X₂ is N andthe other is NH or N—OH may be prepared as illustrated in Scheme 1 forcompounds wherein X₁ is N and X₂ is NH or N—OH. Using the methoddetailed in U.S. Pat. No. 3,940,486, N-methoxy-N-methylaryl amide isalkylated with the anion generated from a 2(6)-methylpyridine to give aketone. The ketone is treated with sodium nitrite to form the oximewhich is condensed with an aldehyde and NH₄OAc to give a hydroxyimidazole. The hydroxy imidazole may then be reduced withtriphenylphosphite by the method described in U.S. Pat. No. 5,656,644 togive the corresponding imidazole.

Alternatively, the ketone may be oxidised to a diketone with HBr inDMSO. This diketone can then be condensed with a suitably substitutedbenzaldeyde and ammonium acetate to give the imidazole according to themethod outlined in WO 98/56788 and as illustrated in Scheme 2 forcompounds wherein X₁ is N and X₂ is NH.

Non-selective alkylation of the imidazole nitrogen (using one of theprocedures outlined in N. J. Liverton et al; J. Med. Chem., 1999, 42,2180-2190) with a compound of formula L—R′ wherein L is a leaving group,e.g. halo, sulfonate or triflate, will yield both isomers of thecompounds where one of X₁ or X₂ is NR′ wherein R′ is C₁₋₆alkyl, orC₃₋₇cycloalkyl, as illustrated in Scheme 3, the isomers can be separatedby chromatographic methods.

Compounds of formula (I) wherein one of X₁ and X₂ is N and the other isO may be prepared according to Scheme 4. The oximino ketone may bereduced via catalytic hydrogen to afford the amino ketone which can befurther reacted with an appropriately substituted benzoyl chloridecompound. Reaction of the amide product with thionyl chloride affordsthe oxazole product.

Compounds of formula (I) where one of X₁ and X₂ is CH or CHR′ may beprepared according to Scheme 5. A suitably substituted acetophenone anda benzaldehyde are condensed under basic conditions to afford the enonealdol product. This enone is then reacted with apyridine-2-carboxaldehyde under sodium cyanide catalysis to afford the1,4-diketone which is condensed with ammonium acetate to afford thepyrrole.

During the synthesis of the compounds of formula (I) labile functionalgroups in the intermediate compounds, e.g. hydroxy, carboxy and aminogroups, may be protected. A comprehensive discussion of the ways inwhich various labile functional groups may be protected and methods forcleaving the resulting protected derivatives is given in for exampleProtective Groups in Organic Chemistry, T. W. Greene and P. G. M. Wuts,(Wiley-Interscience, New York, 2nd edition, 1991).

Further details for the preparation of compounds of formula (I) arefound in the examples.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable salts thereof.

The invention further provides the use of a compound of formula (I) or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disease mediated by the ALK5 receptorin mammals.

The invention further provides a method of treatment of a diseasemediated by the ALK5 receptor in mammals, comprising administering to amammal in need of such treatment, a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

ALK5-mediated disease states, include, but are not limited to, chronicrenal disease, acute renal disease, wound healing, arthritis,osteoporosis, kidney disease, congestive heart failure, ulcers, oculardisorders, corneal wounds, diabetic nephropathy, impaired neurologicalfunction, Alzheimer's disease, trophic conditions, atherosclerosis, anydisease wherein fibrosis is a major component, including, but notlimited to peritoneal and sub-dermal adhesion, lung fibrosis and liverfibrosis, and restenosis.

By the term “treating” is meant either prophylactic or therapeutictherapy.

The invention further provides a method of inhibiting the TGF-βsignaling pathway in mammals, for example, inhibiting thephosphorylation of smad2 or smad3 by the type I or activin-like kinaseALK5 receptor, which method comprises administering to a mammal in needof such treatment, a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

The invention further provides the use of a compound of formula (I) or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for inhibiting the TGF-β signaling pathway in mammals.

The invention further provides a method of inhibiting matrix formationin mammals, for example, by inhibiting the phosphorylation of smad2 orsmad3 by the type I or activin-like kinase ALK5 receptor, which methodcomprises administering to a mammal in need of such treatment, atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

The invention further provides the use of a compound of formula (I) or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for inhibiting matrix formation in mammals.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof, may be administered in conventional dosage forms prepared bycombining a compound of formula (I) with standard pharmaceuticalcarriers or diluents according to conventional procedures well known inthe art. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.

The pharmaceutical compositions of the invention may be formulated foradministration by any route, and include those in a form adapted fororal, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

It will be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of formula (I)will be determined by the nature and extent of the condition beingtreated, the form, route and site of administration, and the particularmammal being treated, and that such optimums can be determined byconventional techniques. It will also be appreciated by one of skill inthe art that the optimal course of treatment, i.e. the number of dosesof the compound of formula (I) given per day for a defined number ofdays, can be ascertained by those skilled in the art using conventionalcourse of treatment determination tests.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable salt thereof is administered in theabove-mentioned dosage range.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following examples are to be construed as merely illustrative andnot a limitation on the scope of the invention in any way. In theExamples, unless indicated otherwise, mass spectra were performed usingan Hitachi Perkin-Elmer RMU-6E with chemical ionization technique (CI)or a Micromass Platform II instrument with electrospray (ES) ionizationtechnique.

EXAMPLES Example 1:4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1-hydroxy-1H-imidazol-2-yl]benzonitrile

The title compound was prepared using the method in U.S. Pat. No.3,940,486 to prepare2-(t-butyl)4-(phenyl)-N-1-hydroxy-5-(4-pyridyl)imidazole except using2-hydroxyimino-2-(2-pyridyl)-(4-fluoro)-acetophenone and4-cyanobenzaldehyde. ESMS (M+H)⁺=357.1.

Example 2:4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzonitrile

The title compound was prepared using the procedure in U.S. Pat. No.5,656,644 (Example 1) to prepare2-(4-cyanophenyl)4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole exceptusing2-(4-cyanophenyl)4-(4-fluorophenyl)-N-1-hydroxy-5-(2-pyridyl)-imidazole.ESMS (M+H)⁺=341.2.

Example 3: 4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoicacid

The title compound was prepared using the procedure in U.S. Pat. No.5,656,644 (Example 9) to prepare 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2yl]benzoic acid exceptusing 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile.ESMS (M+H)⁺=360.1.

Example 4: Methyl4-[4-(4-fluorophenyl)-5-(2-pyridyl)-imidazol-2-yl]benzoate

Material from Example 3 was heated at reflux in a solution ofmethanol/sulfuric acid for 18 h. The solution was concentrated to removethe methanol and the resulting aqueous solution was extracted withchloroform to yield the title compound. ESMS (M+H)⁺=374.2.

Example 5: Ethyl4-[4-(4-fluorophenyl)-5-(2-pyridyl)-imidazol-2-yl]benzoate

Material from Example 3 was heated at reflux in a solution ofethanol/sulfuric acid for 18 h. The solution was concentrated to removedthe ethanol and the resulting aqueous solution was extracted withchloroform to yield the title compound. ESMS (M+H)⁺=388.2.

Example 6:4-(4-Benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)-benzonitrile

The title compound was prepared using the procedure of Example 1 exceptusing 1-benzo[ 1,3]dioxol-5-yl-2-pyridin-2-ylethane- 1,2-dione oxime and4-cyanobenzaldehyde. ESMS (M+H)⁺=383.1.

Example 7:4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile

The title compound was prepared using the procedure of Example 2 exceptreplacing4-[4-(4-fluorophenyl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrilewith4-(4-benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)-benzonitrile.ESMS (M+H)⁺=367.1.

Example 8:4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid

The title compound was prepared using the procedure of Example 3 exceptreplacing 4-[4-(4-fluorophenyl)-5-pyridin-2-yl-1H-imidazol-2-yl 9benzonitrile with4-(4-benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile. ESMS (M+H)⁺=386.1.

Example 9:2-[4-Benzo[1,3]dioxol-5-yl-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine

The title compound was prepared using the procedure of Example 1 exceptusing 1-benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethane-1,2-dione oxime and4-nitrobenzaldehyde. ¹H NMR (250 MHz; CD₃OD) δ: 5.71 (2H, s), 6.58 (1H,d), 6.73 (2H, m), 7.03 (1H, m), 7.20-7.35 (1H, m), 7.47 (1H, m), 8.00(4H, m), 8.31 (1H, m); m/z (ESMS): 372 [M+H].

Example 10:3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine

The title compound was prepared by tin(II)chloride reduction of2-[4-benzo[1,3]dioxol-5-yl-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine(Example 9). m/z (ESMS): 342. [M+H].

Example 11:4-[4-(4-Fluorophenyl)-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine

The title compound was prepared using the procedure of Example 1 exceptusing 1-(4-fluorophenyl)-2-pyridin-2-yl-ethane-1,2-dione oxime and4-nitrobenzaldehyde. m/z (ESMS): 372 [M+H].

Example 12: 4-[4-(4-Fluorophenyl)-5-pyridin-2-yl-1-imidazol-2-yl)phenylamine

The title compound was prepared by tin(II)chloride reduction of4-[4-(4-fluorophenyl)-2-(4-nitrophenyl)-1H-imidazol-5-yl]-pyridine(Example 11). (ESMS): 342. [M+H].

Example 13:4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenyl]methanol

Methyl 4-(4-benzo[1,3]-dioxol-5-yl-4-pyridin-2-yl)benzoate (204 mg; 0.5mmol) was dissolved in dry tetrahydrofuran (50 ml) under argon andtreated dropwise with a solution of lithium hydride in tetrahydrofuran(1M; 1 ml; 1 mmol). After 1 h, more lithium aluminium hydride solution(1 ml) was added and the resulting mixture stirred until tlc examinationshowed no starting material remaining. Saturated aq. ammonium chloridesolution was added, followed by ethyl acetate and the phases wereseparated. The organic phase was washed with water (×2), saturatedbrine, dried (MgSO₄) and evaporated to dryness under reduced pressure.Trituration of the residue under 60-80° petroleum ether gave a whitesolid, which was collected by filtration, washed with 60-80° petroleumether and dried under reduced pressure (103 mg; 54%). ¹H NMR (250 MHz,CDCl₃) δ: 2.10-2.80(1H, br, exchangeable), 4.73 (2H, s), 6.02 (2H, s),6.94 (1H, d, J=8 Hz), 7.08-7.18 (3H, m), 7.41 (2H, d, J=8 Hz), 7.53 (2H,brm), 7.92 (2H, d, J=8 Hz), 8.53 (1H, d, J=5 Hz); (ESMS) (M+H)⁺=372.4.

Example 14:4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoylchloride hydrochloride (100 mg; 0.23 mmol) was suspended intetrahydrofuran (5 ml) and treated with 0.88 aq. ammonia solution (1 ml)and the resulting mixture stirred at ambient temperature. The titlecompound (42 mg; 48%) was obtained as a brown powder and collected byfiltration, washed with water and dried at 40° C. under reducedpressure. ¹H NMR (250 MHz, CDCl₃) δ: 5.50-6.40 (2H, br, exchangeable),6.03 (2H, s), 6.90 (1H, d, J=8 Hz), 7.15 (3H, m), 7.55 (2H, brm), 7.89(2H, d, J=8 Hz), 8.06 (2H, d, J=8 Hz), 8.54 (1H, brd); (ESMS)(M+H)⁺=385.4.

Example 15:4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile

Prepared according to the method of Example 2 from4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile.¹H NMR (250 MHz, CDCl₃) δ: 4.32 (4H, brs), 6.94 (1H, d, J=8.2 Hz),7.03-7.26 (4H, m), 7.59 (2H, br. s), 7.72 (2H, d, J=8.3 Hz), 8.07 (2H,d, J=8.3 Hz), 8.53 (1H, br. d J=4.6Hz); m/z (API⁺): 381.1 (MH⁺).

Example 16:4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzamide

4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzonitrile(1 g) was dissolved in methanol (200 ml). Potassium carbonate was added(1 g) and the resulting suspension treated dropwise with an aqueoushydrogen peroxide solution (10 ml of 30% w/v solution) at 0° C. Thesuspension was stirred at room temperature for 18 hours then cautiouslypoured into saturated sodium hydrogen sulfite solution (200 ml) at 0° C.The mixture was tested for the presence of oxidant (starch-iodide teststrips) before organic solvent removal by rotary evaporation underreduced pressure. The crude product was digested in ethyl acetate (200ml). The ethyl acetate layer was dried (MgSO₄) and evaporated to drynessunder reduced pressure. The title compound was isolated by silica gelcolumn chromatography (using a 1:9:190 ammonia:methanol:dichloromethanesolution as eluent) as a beige solid (153 mg, 15%). ¹H NMR (250 MHz,CDCl₃) δ: 4.26 (4H, brs), 6.05 (1H, brs), 6.60 (1H, brs), 6.87 (1 H,brd, J=7. 7 Hz) 7.0-7.25 (3H, 7.53 (2H, d, J=3.7 Hz), 7.76 (2H, d, J=8.2Hz), 7.95 (2H, d, J=8.2 Hz), 8.47 (1H, d, J=4.6 Hz); m/z (ESMS): 399(MH⁺).

Example 17:4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzamide

Prepared according to the method of Example 14 from4-[4-(2,3-dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrilewhich was prepared from4-[4-(2,3-dihydro-benzofuran-6-yl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrileaccording to the method of Example 2. ¹H NMR (250 MHz, CDCl₃) δ: 3.27(2H, brt, J=8.5 Hz), 4.63 (2H, brt, J=8.5 Hz), 5.50-5.90 (1H, brs),6.05-6.35 (1H, brs), 7.08-7.20 (3H, m), 7.18-7.30 (3H, m) 7.56 (2H,brs), 8.86 (2H, d, J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz), 8.54 (1H, brd,J=4.5 Hz); m/z (ESMS): 383.5 (MH⁺).

Example 18:3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile

Prepared according to the method of Example 2 from3-(4-benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)-benzonitrile.¹H NMR (250 MHz, CDCl₃) δ: 6.03 (s, 2H), 6.90 (d, 1H, J=8.37 Hz), 7.15(m, 3H), 7.57 (m, 4H), 8.16 (d, 1H, J=7.90 Hz), 8.23 (s, 1H), 8.51 (d,1H); m/z (AP+): 367 (M+H)⁺, 368 (M+2H)⁺.

Example 19:4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile

The title compound was prepared using the procedure of Example 1 exceptusing 1-(2,3-Dihydro-benzofuran-6-yl)-2-pyridin-2-yl-ethane-1,2-dioneoxime and 4-cyanobenzaldehyde. m/z (ESMS): 365 [M+H].

Example 20:4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzamide

Prepared according to the method of Example 16 from4-[4-(2,3-dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrilewhich was prepared from4-[4-(2,3-dihydrobenzofuran-6-yl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrileaccording to the method of Example 2. ¹H NMR (250 MHz, CDCl₃) δ: 3.27(2H, brt, J=8.5 Hz), 4.63 (2H, brt, J=8.5 Hz), 5.50-5.90 (1H, brs),6.05-6.35 (1H, brs), 7.08-7.20 (3H, m), 7.18-7.30 (3H, m) 7.56 (2H,brs), 8.86 (2H, d, J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz), 8.54 (1H, brd,J=4.5 Hz); m/z (ESMS): 383.5 (MH⁺).

Example 21:3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid

3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)-benzonitrile(600 mg, 1.64 mmol) was dissolved in ethanol (20 ml) 2M aq. NaOH (50 ml)was added and the mixture heated at reflux overnight. On cooling, thesolution was acidified to pH 1 with 5M aq. HCl and the precipitatecollected by filtration, washed with water then diethyl ether and driedto afford a yellow/green solid. ¹H NMR (250 MHz, DMSO) δ 6.06 (s, 2H),6.97 (d, 1H), 7.20 (dd, 3H), 7.57 (t, 1H), 7.80 (t, 1H), 7.90 (d, 1H),8.30 (s, 2H), 8.74 (s, 1H), m/z (AP+): 385 (M+H)⁺ 386 (M+2H)⁺.

Example 22:4-[4-(4-Methoxyphenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile

The title compound was prepared using the procedure of Example 1 exceptusing 1-(4-methoxyphenyl)2-pyridin-2-yl-ethane-1,2-dione oxime and4-cyanobenzaldehyde. m/z (ESMS): 353 [M+H].

Example 23:4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzamide

Prepared according to the method of Example 16 except using4-[4-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrilewhich was prepared according to the method of Example 2. m/z (ESMS): 421[M+H].

Example 24:4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide

The title compound was prepared using the procedure outlined in N. J.Liverton et al, J. Med Chem. 1999, 42, 2180-2190 via alkylation ofExample 15 followed by nitrile hydrolysis as described in Example 16. ¹HNMR (250MHz, CDCl₃) δ: 3.74 (3H, s), 4.24 (4H, s), 5.30 (1H, brs), 6.25(1H, brs), 6.74 (2H, d, J=8Hz), 6.95 (1H, dd, J=1,8 Hz), 7.06 (1H, d,J=1 Hz), 7.26 (1H, m), 7.38 (1H, d, J=8 Hz), 7.66 (1H, m), 7.83, (2H, d,J=7 Hz), 7.91 (2H, d, J=7 Hz), 8.77 (1H, d, J=7 Hz); m/z (AP+): 413(M+H)⁺.

Example 25:4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-4-pyridin-2-yl-1H-imidazol-2-yl]benzamide

The title compound was prepared using the procedure outlined in N. J.Liverton et al, J. Med Chem. 1999, 42, 2180-2190 via alkylation ofExample 15 followed by nitrile hydrolysis as described in Example 16. ¹HNMR (250 MHz, DMSO) δ: 3.52 (3H, s), 4.29 (4H, s), 6.92 (2H, s), 6.96(1H, s), 7.14 (1H, m), 7.48 (1H, s), 7.81 (2H, m), 7.83 (2H, d, J=7 Hz),8.02 (2H, d, J=7 Hz), 8.10 (1H, s), 8.34 (1H, d, J=2 Hz); m/z (AP+): 413(M+H)⁺.

Example 26:4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzonitrile

N-(2-Benzo[1,3]dioxol-5-yl-2-oxo-1-pyridin-2-yl-ethyl)4-cyano-benzamide(0.1 g, 0.26 mmol) was dissolved in neat thionyl chloride (10 ml) andheated at reflux temperature for 2 hours. The cooled solution wascautiously added dropwise to a concentrated sodium hydroxide-icemixture. The crude product was extracted into dichloromethane andpurified using hexane-ethylacetate (1:1) as eluent to give the titlecompound (9 mg, 9%). ¹H NMR (CDCl₃) δ: 6.06 (2H, s), 6.84-6.99 (2H, m),7.27-7.31 (1H, m), 7.86 (2H, d, J=7 Hz), 8.00 (2H, d, J=7 Hz), 8.04 (1H,s), 8.23 (1H, dd, J=7 and 1 Hz), 8.42 (1H, d, J=7 Hz), 8.65 (1H, dd, J=7and 1 Hz); m/z (API) 368 (M+H⁺).

Example 27:4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzamide

Prepared from4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)-benzonitrileusing hydrogen peroxide and methanolic potassium carbonate according toExample 16 and isolated in 44% yield. ¹H NMR (DMSO) δ: 6.15 (2H, s),7.08-7.16 (2H, m), 7.45-7.54 (2H, m), 7.95-7.99 (1H, m), 8.02 (1H, br.s), 8.08 (1H, br. s), 8.12-8.15 (2H, m), 8.22 (1H, dd, J=7 and 1 Hz),8.48 (1H, d, J=8 Hz), 8.74 (1H, d, J=8 Hz); m/z (API) 386 (M+H⁺).

Example 28:4(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-pyrrol-2-yl)benzamide

4-(3-Benzo[1,3]dioxol-5-yl-4-oxo4-pyridin-2-ylbutanoyl)benzamide (1.69g; 4.2 mmol) and ammonium acetate (2.1 g; 27.3 mmol) were reactedtogether according to the method described in Bioorg. Med. Chem.Letters, 1998, 8, 2689-2694. The title compound was isolated as a brownpowder from methanol (126 mg; 8%). ¹H NMR (DMSO) δ: 6.04 (2H, s),6.82-6.93 (4H, m), 7.18-7.32 (3H, m), 7.63-7.74 (1H, m), 7.86-7.96 (5H,m), 8.61 (1H, d, J=4 Hz), 11.63 (1H, brs); m/z (LCMS): 383.9 (M+H)⁺.

INTERMEDIATES Preparation 1:1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-pyridin-2-yl-ethanol

Diisopropylamine (18.8 ml, 1.1 equiv) was dissolved in dry THF (200 ml)under argon and cooled to −78° C. n-Butyl lithium in hexane (2.5M→53.6ml, 1.1 equiv.) was added, followed by a dropwise addition of 2-methylpyridine (12.0 ml, 1 equiv). The reaction mixture was stirred for 15minutes at −78° C. and was then treated with1,4-benzodioxan-6-carboxaldehyde (20 g, 121.8 mmol) in dry THF (50 ml).The reaction mixture was stirred at −78° C. for 30 min then allowed toreturn to room temperature overnight.

Excess saturated aqueous ammonium chloride was added to the mixturefollowed by 200 ml EtOAc. The organic phase was separated and washedwith 2M NaOH (2×150 ml), H₂O (3×100 ml), brine (100 ml) dried (MgSO₄)and evaporated to dryness. (31.6 g, quantitative). ¹H NMR (400 MHz,CDCl₃) δ: 3.07 (d, 2H), 4.20 (s, 4H), 5.03 (m, 1H), 5.57 (brs, 1H), 6.81(d, 1H), 6.85 (d, 1H), 6.94 (s, 1H), 7.09-7.14 (m, 2H), 7.57 (t, 1H),8.46 (s, 1H). m/z (ES+): 258 (M+H)⁺, 240 (M−OH)⁺.

Preparation 2:4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoylchloride hydrochloride

4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid(379 mg; 0.98 mmol) was suspended in dry dichloromethane (20 ml) underargon and treated sequentially with oxalyl chloride (0.1 ml) thenN,N-dimethylformamide (1 drop). The mixture was stirred at ambienttemperature for 1 h. More oxalyl chloride (2×0.1 ml) was added at 1 hand 2 h and the mixture stirred at ambient temperature for 5 h.Volatiles were removed under reduced pressure to give the title compoundas an orange powder: m/z (methyl ester; API): 400.3 (M+H)⁺.

Preparation 3: 2,3-Dihydro-benzofuran-6-ol

6-Hydroxy-2H-benzofuran-3-one (3 g) was suspended in anhydroustetrahydrofuran under an argon atmosphere and cooled to 0° C. Lithiumaluminium hydride (20 ml of a 1M solution in tetrahydrofuran) was addeddropwise over 10 min and the reaction allowed to reach room temperatureover 2 hours. The reaction was cooled to 0° C. and treated dropwise withsaturated ammonium chloride solution. Ethyl acetate (200 ml) was addedand the mixture filtered through Celite. The ethyl acetate layer wasseparated, dried (MgSO₄) and evaporated to dryness under reducedpressure. The resulting mixture of 2,3-dihydro-benzofuran-3,6-diol andbenzofuran-6-ol (approximately 1:1 by 250 MHz ¹H NMR) was dissolved in amixture of hydrochloric acid (200 ml, 5M aqueous solution) and methanol(300 ml) and palladium hydroxide (0.5 g) added. The mixture was stirredunder a hydrogen atmosphere for 3 hours then filtered through Celite.The organics were removed by evaporation under reduced pressure and theresulting solution neutralised with concentrated anmmonia solution. Theproduct was extracted into dichloromethane. The dichloromethane solutionwas dried (MgSO₄) and evaporated to dryness under reduced pressure toyield the title compound (2.5 g, 92%). ¹H NMR (250 MHz, CDCl₃) δ: 3.11(2H, t, J=8.4 Hz), 4.57 (2H, t, J=8.4 Hz), 6.27-6.34 (2H, m), 6.92-7.02(1H, m); m/z (API+): 139.1 (M+3H⁺).

Preparation 4: Trifluoro-methanesulfonic acid2,3-dihydro-benzofuran-6-yl ester

2,3-Dihydro-benzofuran-6-ol (2.5 g) was dissolved in anhydrousdichloromethane under an argon atmosphere. Triethylamine (3.5 ml) wasadded and the reaction cooled to 0° C. A solution of trifluoromethanesulfonic anhydride (3.1 ml) in dichloromethane (10 ml) was addeddrop-wise over 1 minute. After 2 hours the reaction was quenched by theaddition of a saturated sodium bicarbonate solution (50 ml). Thereaction mixture was partitioned between water (100 ml) anddichloromethane (200 ml). The dichloromethane layer was separated, dried(MgSO₄) and evaporated to dryness under reduced pressure. The resultingresidue was isolated in quantitative yield by silica gel columnchromatography (using 1:3 ethyl acetate:hexane as eluent). ¹H NMR (250MHz, CDCl₃) δ: 3.22 (2H, t, J=8.4 Hz), 4.66 (2H, t, J=8.4 Hz), 6.68 (1H,d, J=1 Hz), 6.74 (1H, dd, J=8 and 1 Hz), 7.20 (1H, d, J=8 Hz); m/z(API⁺): 271(M+3H⁺).

Preparation 5: 2,3-Dihydro-benzofuran-6-carboxylic acid

Palladium bis(triphenylphosphine) dibromide (3 g) was added to adegassed methanolic solution (30 ml) of trifluoro-methanesulfonic acid2,3-dihydro benzofuran-6-yl ester (5 g) and tributylamine (5 ml). Themixture was charged with carbon monoxide at 40 psi in a Berghoffpressure vessel then heated at 100° C. for 72 hours. The resultingmethanolic solution of 2,3-dihydro-benzofuran-6-carboxylic acid methylester was treated with sodium hydroxide solution (50 ml of 2M aqueoussolution) and stirred at room temperature for 18 hours. The reactionmixture was acidified to pH 1 with hydrochloric acid (5M aqueoussolution) and extracted with ethyl acetate (300 ml). The ethyl acetatelayer was separated and the product extracted into saturated sodiumbicarbonate solution (200 ml). The sodium bicarbonate solution wasacidified to pH 1 with hydrochloric acid (5M aqueous solution) and theresulting precipitate dissolved in ethyl acetate. The ethyl acetatelayer was separated, dried (MgSO₄) and evaporated to dryness underreduced pressure to yield the title compound (0.6 g, 20%). ¹H NMR (250MHz, CD₃OD) δ: 3.20 (2H, t, J=8.6 Hz), 4.54 (2H, t, J=8.6 Hz), 7.23 (1H,d, J=8 Hz), 7.25 (1H, brs), 7.49(1H, dd, J=8 and 1 Hz).

Preparation 6: 2-Amino-1-benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethanonedihydrochloride

1-Benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethane-1,2-dione 2-oxime (2 g,7.75 mmol) was dissolved in ethanol (100 ml) and hydrochloric acid (2 mlof a 36% solution in water) was added. Palladium on charcoal catalyst(0.5 g) was added and the reaction mixture was stirred under a positivepressure of hydrogen for 1.5 hours. The catalyst was removed byfiltration through Kieselguhr and the resulting filtrate evaporated todryness under reduced pressure. Trituration under anhydrous diethylether gave the title compound as a pale yellow solid (1.5 g, 59%); m/z(API) 257 (M+H⁺, 100%).

Preparation 7:N-(2-Benzo[1,3]dioxol-5-yl-2-oxo-1-pyridin-2-yl-ethyl)4-cyano-benzamide

2-Amino-1-benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethanone dihydrochloride(1 g, 3 mmol) was added to a stirring solution of 4-cyano-benzoylchloride (0.459 g, 3 mmol) in dichloromethane (10 ml). Triethylamine (2ml, 14 mmol) was added dropwise and the reaction was stirred at ambienttemperature for 18 hours. Water was (50 ml) added the organics wereextracted into dichloromethane. Chromatographic purification using adichloromethane solution of ammonia in methanol (0.5% c. ammonia: 4.5%methanol: 95% dichloromethane) yielded the title compound as a paleyellow oil (0.9 g, 76%); m/z (API) 386 (M+H⁺, 100%).

Preparation 8: 4-((E/Z)-3-Benzo[1,3]dioxol-5ylallanoyl)benzamide.

4-Acetylbenzamide (1.3 g; 8 mmol) was dissolved in methanol (50 ml) andpiperonal (1.19 g; 8 mmol) added, followed by 2M aqueous sodiumhydroxide solution (6 ml; 12 mmol). The resulting mixture was left tostand at ambient temperature for 72 h. The crystalline precipitate wascollected by filtration, washed well with water and dried at 40° C.under reduced pressure (1.51 g; 64%); ν_(max) (CH₂Cl₂) 1682, 1651, 1424and 1265 cm⁻¹; ¹H NMR (DMSO) δ: 6.08 (2H, s), 6.96 (1H, d, J=8 Hz), 7.30and 7.33 (1H, dd, J=8 and 1 Hz), 7.54 (1H, br, exchangeable), 7.65 (1H,d, J=1 Hz), 7.67 (1H, d, J=15 Hz), 7.82 (1H, d, J=15 Hz), 7.98 (2H, d,J=8 Hz), 8.15-8.18 (3H, brd); m/z (API): 296 (M+H)⁺.

Preparation 9:4-(3-Benzo[1,3]dioxol-5-yl-4-oxo-4-pyridin-2-ylbutanoyl)benzamide.

4-((E/Z)-3-benzo[1,3]dioxol-5-ylallanoyl)benzamide (1.47 g; 4.98 mmol),pyridine-2-carboxaldehyde (533 mg; 4.98 mmol) and sodium cyanide (24 mg;10 mol %) were mixed together in N,N-dimethylformamide (30 ml) and theresulting mixture heated at reflux for 18 h. The reaction mixture wascooled to room temperature and poured into water with vigorous stirringthen extracted with ethyl acetate. The combined organic extracts werewashed with water, saturated brine, dried (MgSO₄) and evaporated todryness under reduced pressure to give the title compound as a blackfoam (1.69 g; 84%); m/z (API); 403.1 (M+H)⁺.

Biological Data

The biological activity of the compounds of the invention may beassessed using the following assays:

Method for evaluating ALK5 Kinase Phosphorylation of Smad3

Basic Flash-Plates (NEN Life Sciences) were coated by pipetting 100micro liter of 0.1 molar sodium bicarbonate (pH 7.6), containing 150nanograms of the fusion protein glutathion-S-transferase-smad3/100 microliter of coating buffer. Plates were covered and incubated at roomtemperature for 10-24 hours. Then the plates were washed 2 times with200 micro liter of coating buffer (0.1 molar sodium bicarbonate) andallowed to air dry for 2-4 hours.

For the phosphorylation reaction each well received 90 microlitercontaining 50 millimolar HEPES buffer (pH 7.4); 5 millimolar MgCl₂; 1millimolar CaCl₂; 1 millimolar dithiothreitol; 100 micromolar guanosinetriphosphate; 0.5 micro Ci/well gamma³³P-adenosine triphosphate (NENLife Sciences) and 400 nanograms of a fusion protein of glutathion-S-transferase at the N-terminal end of the kinase domain of ALK5(GST-ALK5). Background counts were measured by not adding any GST-ALK5.Inhibitors of ALK5 were evaluated by determining the activity of theenzyme in the presence of various compounds. Plates were incubated for 3hours at 30° C. After incubation the assay buffer was removed byaspiration and the wells were washed 3 times with 200 microliter cold 10millimolar sodium pyrophosphate in phosphate buffered saline. The lastwash was aspirated and blotted plate dry. Plate was then counted on aPackard TopCount.

Inhibition of Matrix Markers: Western Blot Protocol

Data confirming activity in the enzyme assay was obtained as follows.

Cells were grown to near confluence in flasks, starved overnight andtreated with TGF-beta and compounds. Cells were washed at 24 or 48 hoursafter treatment with ice cold phosphate buffered saline, then 500microliter of 2× loading buffer was added to plate and cells werescraped and collected in microcentrifuge tube. (2× loading buffer: 100mM Tris-Cl, pH6.8, 4% sodium dodecyl sulfate, 0.2% bromophenol blue, 20%glycerol, 5% beta-mercapto-ethanol). Cells were lysed in tube andvortexed. Sample was boiled for 10 minutes. 20 microliters of sample wasloaded on 7.5% polyacrylamide gel (BioRad) and electrophoresed.

Size fractionated proteins in gel were transferred to nitrocellulosemembrane by semidry blotting. Membrane was blocked overnight with 5%powdered milk in phosphate buffer saline (PBS) and 0.05% Tween-20 at 4degrees C. After 3 washes with PBS/Tween membranes were incubated withprimary antibody for 4 hours at room temperature. After three washeswith PBS/Tween membrane was incubated with secondary antibody for 1 hourat room temperature. Finally, a signal was visualized with ECL detectionkit from Amersham.

The compounds of this invention generally show ALK5 receptor modulatoractivity having IC₅₀ values in the range of 0.0001 to 10 μM.

What is claimed is:
 1. A compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein R₁ is naphthyl, anthracenyl, or phenyl optionally substitutedwith one or more substituents selected from the group consisting ofhalo, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkyl, —O—(CH₂)_(n)—Ph,—S—(CH₂)_(n)—Ph, cyano, phenyl, and CO₂R, wherein R is hydrogen orC₁₋₆alkyl and n is 0, 1, 2 or 3; or R₁ is phenyl fused with an aromaticor non-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to two heteroatoms, independently selected fromN, O and S; R₂ is H, NH(CH₂)_(n)—Ph or NH—C₁₋₆alkyl, wherein n is 0, 1,2 or 3; R₃ is CO₂H, CONH₂, CN, NO₂, C₁₋₆alkylthio, —SO₂—C₁₋₆alkyl,C₁₋₆alkoxy, SONH₂, CONHOH, NH₂, CHO, CH₂OH, CH₂NH₂, or CO₂R, wherein Ris hydrogen or C₁₋₆alkyl; and one of X₁ and X₂ is N or CR′, and theother is NR′ or CHR′ wherein R′ is hydrogen, OH, C₁₋₆alkyl, orC₃₋₇cycloalkyl; or when one of X₁ and X₂ is N or CR′ then the other maybe S or O.
 2. A compound according to claim 1 wherein R₁ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of halo, C₁₋₆alkoxy, C₁₋₆alkylthio, and phenyl; or R₁is phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7members wherein said cyclic ring optionally contains up to twoheteroatoms, independently selected from N, O and S.
 3. A compoundaccording to claim 1 wherein R₂ is positioned ortho to the nitrogen ofthe pyridyl ring.
 4. A compound according to claim 1 wherein R₃ is CO₂H,CONH₂, CN, NO₂, SONH₂, CONHOH, NH₂, CHO, CH₂OH or CH₂NH₂.
 5. A compoundaccording to claim 1 wherein one of X₁ and X₂ is N or CR′, and the otheris NR′ or CHR′ wherein R′ is hydrogen, C₁₋₆alkyl, or C₃₋₇cycloalkyl,provided that at least one of X₁ and X₂ is N or NR′; or one of X₁ and X₂is N and the other is O.
 6. A compound according to claim 5 wherein oneof X₁ and X₂is N and the other is NR′.
 7. A compound according to claim1 wherein each R′ is hydrogen.
 8. A compound according to claim 1selected from the group comprising:4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1-hydroxy-1H-imidazol-2-yl]benzonitrile;4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzonitrile;4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoic acid;Methyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate;Ethyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate;4-(4-Benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;2-[4-Benzo [1,3]dioxol-5-yl-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine;3-(4-Benzo[1,3]dioxol-5-yl-5 -pyridin-2-yl-1H-imidazol-2-yl)phenylamine;4-[4-(4-Fluorophenyl)-2-(4-nitrophenyl)-1H-imidazol-5 -yl]pyridine;4-[4-(4-Fluorophenyl)-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine;4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenyl]methanol;4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide;4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile;4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;4-[4-(2,3-Dihydro-benzofuran-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;3-[4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzonitrile;4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;4-[4-(4-Methoxyphenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile;4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-4-pyridin-2-yl-1H-imidazol-2-yl]benzamide;4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzonitrile;4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzamide; and4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-pyrrol-2-yl)benzamide; or apharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound according claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.
 10. A method of inhibiting the TGF-βsignaling pathway in mammals, comprising administering to a mammal inneed of such treatment, a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 11.A method for treating a disease selected from chronic renal disease,acute renal disease, wound healing, arthritis, osteoporosis, kidneydisease, congestive heart failure, ulcers, ocular disorders, cornealwounds, diabetic nephropathy, impaired neurological function,Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal andsub-dermal adhesion, any disease wherein fibrosis is a major component,and restenosis, comprising administering to a mammal in need of suchtreatment, a therapeutically effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 12. A method forinhibiting matrix formation in mammals, comprising administering to amammal, a therapeutically effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof.